The invention generally relates to the filtration of liquids, more particularly to high precision separation suitable for use in the pharmaceutical and biotechnology industries. The invention is especially applicable to filtration through a porous membrane sheet or a porous hollow fiber column. With the invention, a variety of separation techniques are handled in a yield-enhancing manner and can be automated, including having the separation proceed until a desired level of concentration or other characteristic or parameter is attained. The invention enhances separation processes such as microfiltration, microparticle coating and washing, ultrafiltration, diafiltration and certain preparative chromatography applications. It also improves yield in automated viral infection of mammalian cells such as in gene therapy research and development, as well as rapid cell separation, protein clarification and protein concentration.
In the pharmaceutical and biotechnology industries, the use of micro-filtration, ultrafiltration, tangential or cross-flow filtration, as well as constant volume diafiltration are well-established methods for the separation of dissolved molecules and/or suspended particulates. Typically, the liquid to be filtered is forced through a porous membrane sheet or a porous hollow fiber column. Such sheets or membranes are commercially available in different pore sizes. Depending upon the selected pore size, molecules or particulates smaller than the average membrane or column pore size will pass, together with solvent for example, through the membrane or hollow fiber walls. These molecules or particulates are collected as filtrate, while the retentate is left behind. In many filtration approaches, such as those incorporating ultrafiltration or other tangential-flow filtration devices, the retentate is repeatedly re-circulated with the objective of improving filtration efficiency and enhancing the yield of the filtrate or permeate.
However, filtration devices tend to clog when used over an extended period of time and must be timely replaced. Clogging of a filtration device occurs when the membrane pores become obstructed, typically with trapped cells, particulate matter, cell debris or the like. This clogging of the pores results in a decreased liquid flow across the porous membrane sheet or hollow fiber column wall. The result is a change in the TMP (trans-membrane pressure) which, if not properly addressed, runs the risk of serious detriment to the operation which incorporates the filtration procedure.
Attempts to address these concerns and difficulties have included the development and use of semi-automated filtration systems. These types of systems utilized either manually controlled recirculation pumps or pumps which are controlled by a timing device which will stop pump action after a preset filtration time has elapsed. It is also typical to monitor line pressure through the use of an analog or a digital pressure gauge, usually located between the pump and the filter device. When the gauge reads a certain line pressure level, typically one specified by the manufacturer of the filter device, the filtration must be stopped and the old filter must be replaced with a new one. At times, it is not possible to accurately predict the time at which the pumping action must be stopped in order to avoid overtaxing the filter device. Accordingly, prior art systems which rely solely on timing are not entirely satisfactory.
Prior art filtration technology such as that referred to above also is disadvantageous because it is typically very labor intensive. This prior technology also has additional, serious shortcomings for safe and efficient operation. One shortcoming is that the filtrate yield is frequently not quantitative because of unpredictable solution particulate loads. Thus, for a given re-circulation volume and pump rate, the filtrate yield may differ from case to case, depending upon the amount of pore-sized particulate suspended in the recirculation solution. Another shortcoming is a direct result of back pressure build up due to clogging and gel layer formation. Rapid back pressure build up at times causes bursting of the filter membrane and/or the filter housing, resulting in costly spillage and/or filtrate contamination. Excessive filter inlet pressure also frequently leads to blow-off of tube connections such as at the filter inlet, resulting in costly spillage of retentate, for example. Because of these types of shortcomings, manual and semi-automated filtration systems need to be constantly monitored, which greatly contributes to the high labor intensity of such approaches.
Filtration arrangements as described in Schick U.S. Pat. No. 5,947,689, incorporated hereinto by reference, provide for quantitative capability with TMP pressure monitoring. Such a filtration approach allows for rapid and safe filtration without concern of losing product, particularly pharmaceutical products or biotechnology products which can be extremely expensive, difficult to replace, and can represent the investment of many hours of prior processing. This patent describes coaxing the maximum life out of a filtration device without running the risk of generating operational conditions which can lead to excessive back pressure build up near the end of the life of the filtration device.
It has been found that, by proceeding in accordance with the present invention, it is possible to achieve quantitative filtration of liquids in an automated, safe, labor unintensive manner, all while enhancing the yield of the operation while determining and maintaining parameter values of the filtration system such as trans-membrane pressure, pump output and beneficial filtration conditions.
The system of the present includes a reservoir which contains the liquid to be filtered, typically including valuable pharmaceutical or biotechnological material which needs to be concentrated or separated from a liquid component, such as a media, a carrier, a reaction solution, or other liquid component and which are in need of separation in accordance with precise filtration techniques. A conduit system directs this liquid into a filtration unit through the action of a processor-controlled pump unit.
In a preferred embodiment, at least one pressure sensor is positioned along the conduit system. The processor-controlled pump unit is capable of maintaining constant trans-membrane pressure and/or pump output, determining optimal filtration conditions, and/or monitoring pressures using a peak pressure mode for determining accurate trans-membrane pressures.
Furthermore, in another preferred embodiment, at least one concentration monitor is positioned along the conduit system capable of monitoring permeate or retentate concentrations. The processor-controlled pump unit accepts the output of such concentration monitors and provides an alarm signal when user-defined concentration limits are exceeded. Alternatively, the process-controlled pump unit will respond to the changing output of such concentration monitors by activating conduit valves, thereby allowing reagents to be added to the system or retentate/permeate to be diverted.
It is a general object of the present invention to provide an improved automated, quantitative liquid filtration apparatus and method suitable for precisely handling filtration of pharmaceutical and/or biotechnology materials.
Another object of the present invention is to provide an improved apparatus and method for exacting filtration of liquids through a constant pressure mode which enhances yield of collected components.
Another object of this invention is to provide an improved apparatus and method for the filtration of liquids which vary filter inlet pressure in accordance with a varying level of resistance to flow (increase in fluid viscosity) which develops within the system, particularly the filtration unit.
Another object of the present invention is to provide an improved liquid filtration system and method which are automated and need not be constantly monitored by an operator, thereby being characterized as having very low labor intensity.
Another object of the present invention is to provide improved filtration which includes the use of logic data flow which adjusts pump output in response to changing viscosity of the liquid being filtered.
Another object of the present invention is to provide an improved concentration system or method for adjusting filter retentate output flow in order to maintain optimal product flow in response to changing product characteristics, e.g. increase in fluid viscosity due to removal of solvent.
Another object of the present invention is to provide an improved liquid filtration system which includes the use of flow-through (concentration) detectors, including pH, conductivity, trubidity, UV, and fluorescence detectors for monitoring and controlling the progress and safety of tangential flow filtration procedures.
Another object of the present invention is to provide an improved liquid filtration system which includes the use of flow-through detector outputs to control filtration system configuration in response to changes in permeate or retentate concentration in order to enhance filtration yield and safety.
Another object of the present invention is to provide an improved liquid filtration system which includes the use of serial communication protocols and hardware for remote control and programming (uploading and downloading of filtration programs) of the processor-controlled pump unit as well as reporting of filtration data parameters to remote supervisory sites, which capability is important when the processor-controlled pump unit is located in an access-limited clean room.